G-alkoxy-x-methylhexyne-z-diol-l



Patented June 5, 1951 UNITED STATES PATENT OFFICE6-ALKOXY-4-METHYLHEXYNE-2-DIOL-1A, AND ESTERS THEREOF AND PROCESS MelvinS. Newman, Columbus, Ohio, assignor to Ohio State University ResearchFoundation, Columbus, Ohio, a corporation of Ohio No Drawing.Application May 10, 1947, Serial No. 747,178

where R is a lower alkyl group and where Y is a hydroxyl or an esterthereof and to methods for their preparation.

The products of this invention are of value in the further synthesis ofother chemical compounds and are of particular value in synthesesleading to the preparation of vitamin A and derivatives of vitamin A.Prior to this invention, the products of this invention have not beenknown nor have there been any recognized methods for their preparation.

By this invention I synthesize alkoxy methylhexyne diols and theiresters. The alkoxy methylhexyne diols which I have synthesized all hadalkoxy groups.

By the use of the word alkoxy in the last sentence, elsewhere in thisspecification and in the claims, I mean a compound having an alkyl groupattached to the remainder of the molecule by oxygen where the alkylgroup has not more than six carbon atoms and I so define the term alkoxywherever used herein. Compounds having an alkyl group with more thanfour carbon atoms but not more than six carbon atoms are operative andcompounds having such an alkyl group with more than six carbon atoms maybe operative but in later manipulations, the compounds involved may bemore difficult to handle due to the higher temperatures necessary.

An object of this invention is the preparation of new intermediatechemical compounds useful in synthesizing vitamin A, ethers thereof,similar compounds and other chemicals.

A further, object of the invention is the provision of new methods ofsynthesizing various intermediates and other chemicals.

A further object of this invention is the preparation of a6-alkoxy-4-methy1hexyne-2-dio1-1,4.

A further object of this invention is the provision of methods for thepreparation of a 6- alkoxy-al-methylhexyne-2-diol-1,4.

A further object is the preparation of monoesters of a6-alkoxy--l-methylhexyne-2-diol-1,4.

A further object is the provision of methods for the preparation ofmonoesters of a 6-alkoxy-4- methylhexyne-Z-diol-Li.

The process of my invention may be more readily understood by referenceto the following il- 2 lustrative equations, where R has the value givenabove, and where equations 1 to 4 illustrate the use of a magnesiumhalide reagent while equations 5 to 8 illustrate the use of a lithiumre- In general the process of this invention comprises the reaction ofan organo-metal derivative with propargyl alcohol to prepare a propargylalcohol metal derivative; a metal atom replacing the hydrogen of thehydroxyl group and another replacing the acetylenic hydrogen. The metalderivative is then reacted with an alkoxy butanone, to give a metalcomplex addition prod not. The metal complex addition product is thenhydrolyzed to give an alkoxy methylhekyne diol. The alkoXy methylhexynediol may be reacted with an organic acid, acid halide, or acid anhydrideto give an acyloxy hydro'xy alkoxy methylhexyne.

Among the metals suitable for the formation of a C-M derivative ofpropargyl alcohol are magnesium and lithium as given in the aboveexamples; other alkali metals such as sodium and potassium; alkalineearth metals such as calcium, magnesium halide residues (MgX) and othermetals. The metal derivatives of propargyl alcohol are suitably made byreacting propargyl alcohol with another suitable organo rnetalderivative which will exchange the acetylenic hy drogen. Suitablereagents for the preparation of the propargyl metal derivatives are theGrignard Reagents (R'MgX) (where R is a hydrocarbon radical) and metalalkyls (RIM) (Where M may be any of the metals mentioned above) althoughthe preferred reagents are magnesium reagents and phenyl and butyllithium, it being understood, however, that others are within the scopeof this invention. The hydrogen of the alcohol is also exchanged for themetal in the same manner as the acetylenic hydrogen, but theoxygen-metal derivative so formed does not undergo the additionreactions as does the carbon-metal derivatives. The metal attached tothe carbon upon reaction with the butanone becomes an oxygenmetal group.Both oxygen-metal derivatives are converted to hydroxyl upon hydrolysis.These metalation reactions are preferably carried out in suitablesolvents. For this purpose the solvent must be inert (i. e. having noreplaceable hydrogen or other reactive group) and must also beanhydrous. Ethers such as diethyl ether, dibutyl ether, andtetrahydrofurane and hydrocarbons such as pentane, he'xane, benzene andtoluene are among the solvents which are inert and can be obtainedanhydrous. Diethyl ether or a mixture of diethyl ether andtetrahydrofurane are preferred solvents in which the reaction may beconducted.

The hydrolysis of the addition complex resulting from the addition ofthe propargyl metal derivative and the ketone is preferably done withwater. If desired, the reaction may be cooled during the hydrolysis.When water alone is used, metal hydroxides and basic metal salts mayprecipitate which may make isolation of the product difficult. Theaddition of small quantities of acids such as hydrochloric, sulfuric andacetic or small quantities of inorganic salts such as ammonium salts tothe water used for hydrolysis is advantageous as it renders theseprecipitates water soluble or otherwise easily removed. The preferredembodiment of this invention provides for the use of such an agentduring hydrolysis, but of such kind and in such amount that it will notreact with any of the constituents of the reaction mixture in any way soas to lead to products other than those which are an object of thisinvention.

The esterification of the hydroxyl group on carbon atom number one isaccomplished by an acid or acid derivative such as an acid halide orradical such as alkyl, cycloalkyl, aralkyl, and aryl. In the preferredembodiment of this invention, R is a lower alkyl group such as onehaving four carbon atoms or less. Other hydrocarbon radicals areoperative but in subsequent reactions the compounds involved may be morediflicult to handle due to higher boiling temperatures.

EXAMPLE I A solution of 112 g. (2 moles) of propargyl alcohol in 400 cc.of dry ether was added dropwise over three hours to 2710 cc. of astirred solution of 1.57 N (4.25 moles) butylmagnesium chlorwe in ether.The solution was 'stirred atroom temperature for an additional hour andthen a solution of 224 g. (2.2 moles) of 4-metho'xybuta'none-2 addedover a period of two hours. After stirring overnight, the solution washydrolyzed with 700 cc. of saturated ammonium chloride solution.Theether layer separated concentrated and the residue distilled underreduced pressure. V r V, W v V I The product was obtained as a yellowishoil,

B. P. 122-125 C. at 1 to 2 mm; yie1d=l32;5 g. (42%); n 1.4744.Analysis.'--Calcd. for Gil-11403: Found: 'C,61.3, 61.2; H, 9.3, 9.1. Theproduct has the following formula:

structural CH oHFcE'o-e-onz-omoom In addition, 3'7 g. (33% of propargylalcohol) (B. P. 109-1ll C.) was recovered from the low boilingfractions.

EXAMPLE II Preparation o .i-acetoxy-d methorcy-b methyZhexyn-Z-oZ-al thefollowing structural formula:

on, CHa(|'JOCHz-CEC -'CH -CH;OCH

Whilethe forms of embodiments of the present invention as hereindisclosed constitute preferred forms, it is to be understood that otherforms might be adopted, all coming within the scope of the claims whichfollow.

I claim: 1. As a composition of matter, a compound represented by theformula where R is a lower alkyl group having not more than six carbonatoms.

2. A composition of matter represented by the formula 3. In a method forthe production of compounds represented by the formula wherein R is thelower alkyl group, the step of reacting a propargyl metal derivativewith a 1-alkoxy-3-butanone where the alkoxy group comprises an alkylgroup attached to the remainder of the molecule by oxygen and where thealkyl group has not more than six carbon atoms.

4. In a method of producing compounds represented by the formula whereinR. is the lower alkyl group, the step of reacting a propargyl metalderivative with a l-alkoxy-3-butanone where the alkoxy group consists ofan alkyl group attached to the remainder of the molecule by oxygen andwhere the alkyl group has not more than six carbon atoms; andhydrolyzing the reaction product.

5. A method of producing compounds represented by the formula wherein Ris the lower alkyl group comprising reacting a propargyl metalderivative with a l-alkoxy-B-butanone where the alkoxy group consists ofan alkyl group attached to the remainder of the molecule by oxygen andwhere the alkyl group has not more than six carbon atoms; hydrolyzingthe reaction product; and isolating a6-alkoxy-4-methylhexyne-2-dio1-1,4.

6. A method as in claim 3 where the propargyl metal derivative is alithium derivative.

'7. A method for the production of fi-methoxy- 4-methylhexyne-2-diol-1,4comprising reacting a propargyl metal derivative with 1-methoxy-3-butanone; hydrolyzing; and isolating the reaction product.

8. In a method for the production of 1-acyloxy-4-hydroxy-6-alkoXy-4-methylhexyne-2, the steps of reacting a propargylmetal derivative with a 1-alkoxy-3-butanone where the alkoxy radicalconsists of an alkyl group attached to the remainder of the molecule byan oxygen and where the alkyl group has not more than six carbon atoms;hydrolyzing; and acetylating the product so obtained to give the productdesired.

9. In a method for the production ofl-acyloxy-4-hydroxy-6-alkoxy4-methylhexyne2, the step of acetylating a6-alkoxy-4-methylhexyne- 2-diol-1,4, where the alkoxy radical consistsof an alkyl group attached to the remainder of the molecule by an oxygenatom and where the alkyl group has not more than six carbon atoms byreaction with a compound of the group consisting of organic acids, acidhalides, and acid anhydrides.

10. A method for the production of a fi-alkoxy-4-methylhexyne-2-diol-1,4 comprising forming a propargyl metalderivative; reacting the derivative so formed with l-alkoxy-B-butanonewhere the alkoxy group consists of an alkyl group attached to theremainder of the molecule by oxygen and where the alkyl group has notmore than six carbon atoms; and hydrolyzing.

11. A method for the production of al-acyloxy-4-hydroxy-6-alkoxy-4-methylhexyne-2 comprising the step ofreacting a propargyl metal derivative with a l-alkoxy-3-butanone wherethe alkoxy group consists of an alkyl group attached to the remainder ofthe molecule by oxygen where the alkyl group has not more than sixcarbon atoms, and where the alkoxy carbon has at least one hydrogensubstituent.

12. A method for the production of al-acyloxy-4-hydroxy-6-alkoxy-4-methy1hexyne-2 comprising the steps offirst reacting a propargyl metal derivative with a 1-alkoxy-3-butanonewhere the alkoxy group consists of an alkyl group attached to theremainder of the molecule by oxygen, where the alkyl group has not morethan six carbon atoms, and where the alkoxy carbon has at least onehydrogen substituent and second hydrolyzing the reaction product.

13. A method for the production of al-acyloxy-4-hydroxy-6-alkoxy-4-methylhexyne-2 comprising the steps offirst reacting a propargyl metal derivative with a 1-alkoxy-3-butanonewhere the alkoxy group consists of an alkyl group attached to theremainder of the molecule by oxygen, where the alkyl group has not morethan six carbon atoms, and where the alkoxy carbon has at least onehydrogen substituent; second hydrolyzing the reaction product; and thirdisolating the hydrolyzed product.

14. In a method for the production of intermediate compounds, a step ofreacting a propargyl halomagnesium derivative with a1-alkoxy-3-butanonewhere the alkoxy group consists of an alkyl groupattached to the remainder of the molecule by oxygen and where the alkylgroup has not more than six carbon atoms.

MELVIN S. NEWMAN.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,253,342 Mikeska et a1 Aug. 19,1941 2,369,157 Milas Feb. 13, 1945 2,369,159 Milas Feb. 13, 19452,382,085 Milas Aug. 14, 1945 2,382,086 Milas Aug. 14, 1945 2,412,465Milas Dec. 10, 1946

1. AS A COMPOSITION OF MATTER, A COMPOUND REPRESENTED BY THE FORMULA